The haemoflagellate parasites of man, despite their close taxonomic relationship within the family Trypanosomatidae, a shared range of morphological types, and common elements of structure and biochemistry, cause a diverse variety of diseases including African and American trypanosomiasis, and leishmaniasis (a person was reportedly exposed to leishmania while in Ireland, an area previously thought to be free of leishmania). This diversity is partially a reflection of the different extracellular and intracellular sites of development adopted by these trypanosomatids. Currently available compounds for use against such parasites suffer from various drawbacks, most notably their unacceptable toxicity.
A considerable effort is currently underway to find more efficacious and less toxic compounds for the clinical treatment of leishmaniasis and trypanosomiasis. A proliferation of studies on the chemotherapy of Leishmania and rational biochemical approaches in studies on Trypanosoma brucei have recently produced promising new leads, but many of the problems associated with the treatment of South American trypanosomiasis (Chagas disease) remain intractable.
Hairy leukoplakia is apparently unique to patients infected with HIV. It consists of white warty like projections occurring particularly on the lateral aspects of the tongue and the cheeks. Its cause is unknown, but electron microscopic studies suggest that a virus (possibly Epstein-Barr or the human papilloma virus) may be implicated. Although it is usually painless, its unsightliness worries many patients.
One of the hardest problems confronting the physician dealing with a patient with HIV antibodies is the difficulty of predicting which patients will progress to AIDS. But there are both clinical features and laboratory markers which may help. Clinical features of a poor prognosis are oral candidosis, herpes, herpes zoster, hairy leukoplakia, and the presence of fever, malaise, diarrhoea, or weight loss.
It is believed that human infection by the family of retroviruses known as HIV is deleterious to the health of infected persons. Examples of viruses which are currently believed to belong to the HIV family are the lymphadenopathy-associated virus (LAV) and the human T-lymphotrophic virus type III (HTLV-III). LAV and HTLV-III, which were discovered independently of each other, are now known to be the same virus and are referred to as HIV-I. Although much is known about modes of transmission of such viruses from person to person, (THE NATURAL HISTORY OF HIV INFECTION IN A COHORT OF HOMOSEXUAL AND BISEXUAL MEN: A DECADE OF FOLLOW UP. Nancy A. Hessol, G. W. Rutherford, A. R. Lifson, P. M. O'Malley, Dept. of Public Health, San Francisco, CA) there is currently controversy regarding particular interactions between the virus and the host cells in which they reside. Generally, a person who is infected by HIV develops antibodies to the virus and at some point, the immune system of the person becomes damaged and becomes ineffective in defending the body from diseases. This condition has come to be known as Acquired Immune Deficiency Syndrome, or AIDS. Eventually, because of the immune deficiency of his or her body, an AIDS patient is overcome by one or more of a group of opportunistic infections, for example, Kaposi's Sarcoma and pneumocystis.
There is evidence that macrophage/monocyte infection is a factor in the progression of HIV infection, in initiating the brain damage that is known to occur in AIDS patients, and in triggering the collapse of the immune system as evidenced by eventual profound depletion of T4 lymphocytes. It has been demonstrated using anti-HIV p24 antibody that monocyte/macrophages can be infected with HIV. Up to 70% of cells from individual donors could be infected (Crowe et al., AIDS Research and Human Retroviruses 3, no. 2, (1987) 135). Nicholson et al. have proposed an HIV-III /LAV-induced effect in monocyte function rather than (or in addition to) an intrinsic defect in surviving T cells to account for observed abnormalities in T cell assays that are monocyte-dependent such as pokeweed mitogen-induced antibody synthesis and proliferative responses to soluble antigens. These T cell assays have previously been reported as abnormal even when assayed as T cell subsets (The Journal of Immunology, 137, No. 1, (1986) 323).
Since it is well established that one of the first events that occurs when a foreign material (for example, a virus) enters the body is its uptake by mononuclear phagocytes, it is conceivable that these cells represent a primary target for HIV. Gartner et al. have shown that virus production by HTLV-III/LAV infected macrophages was high and long-lived, indicating that these cells may play a role in virus dissemination and persistence. They have demonstrated HTLV-III/LAV replication in macrophages was fully productive in the situations they evaluated (Science 233 (1986) 215).
Salahuddin et al. observed that in-vitro pulmonary macrophages can be infected with HTLV-III and appear to be less susceptible to the phytopathic effects of this retrovirus, which suggests that tissue macrophages should be considered as potential reservoirs of HTLV-III in-vitro (Blood 68, No. 1, (1986) 281).
Ho D.D. et al observed normal blood-derived monocytes/macrophages were found to be susceptible to infection in-vitro by HTLV-III. In addition, HTLV-III was recovered from monocytes/macrophages of patients infected with this virus. It was postulated therefore that HTLV-III-infected monocyte/macrophages may serve as a vehicle for the dissemination of virus to target organs and as a reservoir for viral persistence, as has been shown for other lentiviruses, including visna virus and caprine arthritis encephalitis virus (J. Clin Invest. 77, (198) 1712).
Anti-viral agents which inhibit replication of viruses have been known since the mid 1960's. (PROSPECTS FOR THE PREVENTION AND THERAPY OF INFECTIONS WITH THE HUMAN IMMUNODEFICIENCY VIRUS. Markus Vogt, Martin S. Hirsch, Infectious Disease Unit, Massachusetts General Hospital, Harvard Medical School, Boston). Several hundred or more of these agents are now known but azidothymidine (AZT, zidovudine) is the only drug which has received approval from the Federal Drug Administration in the United States for treatment against the virus of people with AIDS. The use of AZT in the treatment of AIDS patients suffers from many deficiencies. AZT is very expensive. Treatment with AZT often causes side effects in persons being treated with it and often the side effects are so severe that treatment with it must be halted altogether. (DEVELOPMENT OF HIV-VARIANTS WITH HIGHER RESISTANCE AGAINST AZT UNDER TREATMENT WITH AZT. F. Zimmermann, L. Biesert, H von Briesen, Klinikum der Universitat, Frankfurt, FRG.) The long term effectiveness of treatment with AZT of AIDS patients is still unknown, although it is believed that AZT treatment will not result in the elimination of the virus from the body of an infected person. There is evidence that AZT-resistant strains of HIV are developing in AIDS patients being treated with AZT (F. Zimmermann and L. Biesert).
As a further background to particular aspects of the present invention, the compound N.sup.6 - (.DELTA..sup.2 -isopentenyl) adenosine, (IPA), which has formula Ia, illustrated below, has been used previously in clinical trials involving the treatment of cancer. (CYTOKININS AS CHEMOTHERAPEUTIC AGENTS, Annals of the New York Academy of Science, 25, 225-234 Mittleman, Arnold et al. (1975)). IPA is a naturally occurring compound. For example, it has been shown to be an anticodon-adjacent nucleoside in certain t-RNAs (N.sup.6 - (.DELTA..sup.2 - ISOPENTENYL) ADENOSINE: THE REGULATORY EFFECTS OF A CYTOKININ AND MODIFIED NUCLEOSIDE FROM t-RNA ON HUMAN LYMPHOCYTES. Biochimica et Biophysica Acta, 281:488-500. Gallo, Robert C., et al. (1972)). IPA has been shown to have cytokinin properties, (Mittleman, et al.) to inhibit the growth of human leukemic myeloblasts, to inhibit the growth of cultured lymphocytes stimulated by phytohemagglutinin (PHA) at certain concentrations and to stimulate the growth of cultured lymphocytes stimulated by PHA at lower concentrations (Gallo, et al.). Further, IPA has been used in clinical experiments on humans as a chemotherapeutic agent (Mittleman, et al.).